Note: This guideline has been updated. The National Guideline Clearinghouse (NGC) is working to update this summary.

Resectable rectal cancer

Assessment of Therapeutic Effectiveness
Treatment

Gastroenterology
Oncology
Radiation Oncology
Surgery

Physicians

To evaluate if patients with resectable rectal cancer should receive preoperative radiotherapy to improve survival and prevent or delay local recurrence and if preoperative radiotherapy should replace the present common practice of postoperative combined radiotherapy and chemotherapy

Adult patients with clinically resectable rectal cancer

Note: This report does not consider the use of preoperative radiotherapy to convert locally advanced, initially unresectable rectal cancer to resectable cases, to preserve the anal sphincter, or to delay the need for colostomy.

1. Preoperative radiotherapy
2. Surgery alone
3. Postoperative adjuvant radiotherapy
4. Preoperative radiotherapy plus chemotherapy
5. Preoperative radiotherapy with surgery
6. Alternative preoperative radiotherapy regimens

• Survival/mortality rates
• Local failure rates
• 30-day postoperative mortality
• Tumour resectability
• Tumour downstaging
• Adverse effects

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases

Original Guideline: December 2002

Twenty-four trials and two meta-analyses were identified.

January 2004 Update

The updated literature search identified five additional reports.

Expert Consensus (Committee)

Not applicable

Meta-Analysis of Randomized Controlled Trials
Review of Published Meta-Analyses
Systematic Review with Evidence Tables

Original Guideline: December 2002

Trials of preoperative radiotherapy (RT) versus surgery alone were pooled using the software package Metaanalyst^0.998 (J. Lau, Boston, MA, USA). Overall mortality, local failure, tumour resectability, tumour downstaging, and adverse effects were pooled in separate analyses for all studies, where data was available. Reported figures or estimates obtained from tables or graphs were used. For calculation of survival and local failure, all eligible patients were considered in the denominator, based on intention to treat. All deaths at the time of reporting, regardless of cause, were included in survival calculations. Patients with local failure included those with non-resected as well as those with recurrent disease. Only resected cases were considered in the calculation of downstaging.

Data were pooled using the random effects model as the more conservative estimate of effect. Results were expressed as risk ratios (RR) with 95% confidence intervals (CI), where a RR less than 1.0 favours preoperative RT and a RR greater than 1.0 favours surgery alone. Odds ratios (OR) and absolute risk differences (RD) were also calculated.

Heterogeneity of results among trials was expected in view of the different treatments used and populations tested, as well as the wide time interval and geography across which these trials were conducted. For example, the RT prescription may affect the results. RT doses greater than 30 Gy₁₀ are considered necessary and pelvic fields are as effective as extended fields. Moreover, the use of three or more RT beams will lessen toxicity, and short delays of surgery after RT will not demonstrate downstaging. Thus, these factors were investigated with sensitivity analyses to see whether there was an impact on results. Outcomes of predetermined groups of patients were examined initially by the graphic method described by L'Abbe et al. and RR calculated. For sensitivity analyses the following factors were examined:

Treatment effects:

• Biologically effective dose (BED) of RT (less than 30 Gy₁₀ versus equal to or greater than 30 Gy₁₀). BED was calculated using the formula BED=nd (1+d/alpha/beta), where n=number of fractions, d=dose per fraction, alpha/beta=10 for tumour effect and acute reactions and alpha/beta=3 for late reactions, with no time correction (not needed for late reactions) because parameters were not available and usual ranges are quite wide;
• RT fraction size (standard fractions up to 2.5 Gy/day versus high fractions of 5 Gy/day);
• Contemporary radiotherapy prescription, defined as studies employing multiple-field technique and target volume confined to the pelvis (i.e., excluding studies employing parallel pair arrangements or including para-aortics); and
• Delay of surgery after completion of RT (less than seven days versus eight or more days).

Population effects:

• Studies including a range of rectal cancer cases versus those including only advanced disease.

Sensitivity analyses were also performed for all five of the meta-analyses (overall survival, local failure, tumour resectability, downstaging, and adverse effects) considering only trials with high design quality. The quality of the 14 eligible randomized trials of preoperative RT versus surgery alone in operable rectal cancer was scored independently. Five assessors assessed each trial using the Detsky instrument. This questionnaire addresses five domains of study quality: randomization process, outcomes measure, patient eligibility, treatment description, and statistical procedures. The 14 questions on the Detsky instrument can be answered "adequate," "inadequate," or "partial" and scored 1, 0, or 0.5, respectively. The final score of each trial is a ratio of the observed points divided by the total number of questions answered. The results from the five assessors were averaged for a final score. Trials with Detsky instrument scores greater than 0.5 were considered to be of high quality.

January 2004 Update

Where the Metaanalyst^0.998 (Dr. Joseph Lau, Boston, MA, USA) software program was used to perform all meta-analyses and produce all figures in the original guideline, in the manuscript and this update version, Review Manager 4.2.1 (© Update Software) (which is freely available through the Cochrane Collaboration) was used. All figures and tables in this practice guideline have been updated to reflect the latest information as presented in the manuscript.

At the suggestion of one of the peer reviewers, the first bullet under treatment effects was changed to include a correction for time and now reads as follows in both the manuscript and this update:

Biologically effective dose (BED) of RT (less than 30 Gy₁₀ versus equal to or greater than 30 Gy₁₀). BED was calculated using the Linear Quadratic formula and the parameters suggested for time correction (1u):

BED time = nd (1+d/alpha/beta) - gamma/alpha (T – Tk) where n=number of fractions, d=dose per fraction, alpha/beta=10 for tumour effect and acute reactions and alpha/beta=3 for late reactions, gamma/alpha = repair rate set at 0.6 Gy/day and T = total treatment time and Tk = initial delay time set at 7 days.

Expert Consensus

Original Guideline: December 2002

The discussion of the Gastrointestinal Cancer Disease Site Group (DSG) focused on results from recent trials of preoperative radiotherapy (RT) in Europe that demonstrated significant improvements in local failure and survival rates. These results, achieved with a short course of radiation (5 fractions) and with less toxicity than standard longer courses of radiation, have prompted the widespread use of this treatment modality in Europe and more recently in North America. Some treatment centres in Ontario have started phase II studies of preoperative RT, in some cases with concurrent chemotherapy.

There are, however, some concerns about the widespread use of preoperative RT. Some potential risks of the treatment seem preventable. The use of radiation given to smaller volumes and multiple fields, instead of the past practice of two fields, has been shown to decrease both early postoperative morbidity and mortality. The exclusion of patients with poor performance status and those with ischemic changes in the electrocardiogram reduced both mortality and morbidity in the first two months. More difficult to predict is the long-term anorectal dysfunction, which restricts the social life of one third of survivors in some series following both pre- and postoperative adjuvant RT. Another concern is that some of the preoperatively irradiated patients would not have required this treatment based on the postoperative staging of the disease. Furthermore, the prognostic value of the postoperative staging of irradiated patients remains uncertain, particularly if there is downstaging of the disease. The postoperative pathological staging is very important to determine the need for adjuvant chemotherapy, which improves survival and reduces local recurrence.

Is preoperative RT an acceptable option to be offered to patients for adjuvant treatment in resectable rectal cancer? The previous recommendations from this group for patients with resected stages II and III rectal cancer was postoperative radiotherapy plus chemotherapy. This combined treatment has been demonstrated to significantly reduce local failure by 50% (95% confidence interval [CI]; 8% to 73%) and improve patient survival by 42% (95% CI; 8% to 63%) in patients with stage II and III rectal cancer when compared to postoperative RT alone. In similar patients, postoperative RT alone compared to observation after surgery decreased local recurrences by 27% (95% CI; 4% to 45%) but did not improve survival. Postoperative RT alone is, therefore, discouraged. Preoperative RT alone, when compared to surgery, has been shown to decrease local failure by approximately 50% and to improve survival by approximately 15%. The improvement in local recurrence occurs even after optimal surgery with total meso-rectal excision (TME). In a single trial, preoperative short-course RT has detected less local recurrence (11% versus 22%, p=0.02) and less morbidity than conventional postoperative RT alone. From these results it can be inferred that preoperative RT is a better treatment choice than postoperative RT plus chemotherapy with less local failures and less morbidity. A comparison of preoperative RT followed by postoperative chemotherapy versus combined postoperative RT plus chemotherapy is presently being investigated in clinical trials but mature results are not yet available for review, and therefore, a definite recommendation cannot be made at this time.

While the guideline developers confirm their recommendation for combined postoperative RT plus chemotherapy for resected patients with stage II and III rectal cancer, based on the evidence from the Swedish and Dutch trials, preoperative RT (followed by chemotherapy for at least patients with stage III) is an alternative provided the patient is made aware of the potential benefits and drawbacks. Benefits are the decrease in local failure and in treatment morbidity. Local failure is an important outcome in rectal cancer as recurrences are associated with significant disability. Drawbacks are the need to use preoperative RT in most patients compared to RT administered according to postoperative staging and the possibility that patients not requiring radiation may develop treatment associated complications.

Physicians should encourage patients to participate in clinical trials of the primary treatment of rectal cancer. These trials should require the best possible surgery, the confirmation of the accuracy of clinical staging versus pathological staging, and the use of measures of quality of life. Patients must also be clearly advised of the differences between treatment approaches.

Not applicable

A formal cost analysis was not performed and published cost analyses were not reviewed.

External Peer Review
Internal Peer Review

Practitioner feedback was obtained through a mailed survey of 155 practitioners in Ontario (30 medical oncologists, 21 radiation oncologists, 100 surgeons, and four gastroenterologists). The survey consisted of 21 items evaluating the methods, results, and interpretive summary used to inform the draft recommendations and whether the draft recommendations should be approved as a practice guideline. Written comments were invited. Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again). The Gastrointestinal Cancer Disease Site Group (DSG) reviewed the results of the survey.

Practitioner feedback indicated a need to clarify the role of preoperative radiotherapy (RT) in the context of the companion guideline recommending postoperative RT plus chemotherapy for stage II and III rectal cancer. In this context, the magnitude of benefits and drawbacks of preoperative and postoperative RT with and without chemotherapy were further discussed.

The revised version of the guideline was circulated to 11 members of the Practice Guidelines Coordinating Committee. Seven members returned ballots: five approved the guideline report as written, and two members approved the guideline conditional on the DSG addressing suggestions for revision. The suggestions referred to the recommendations and the meta-analyses.

These practice guideline recommendations reflect the integration of the draft recommendations with feedback obtained from the external review process. They have been approved by the Gastrointestinal Cancer DSG and the Practice Guidelines Coordinating Committee.

Note: This guideline has been updated. The National Guideline Clearinghouse (NGC) is working to update this summary. The recommendations that follow are based on the previous version of the guideline.

• Preoperative radiotherapy is an acceptable alternative to the standard practice of postoperative radiotherapy for patients with stage II and III resectable rectal cancer.
• Both preoperative and postoperative radiotherapy decrease local recurrence but neither improves survival as much as postoperative radiotherapy combined with chemotherapy. Therefore, if preoperative radiotherapy is used, chemotherapy should be added postoperatively, at least for patients with stage III disease.

None provided

The recommendations are supported by randomized trials and meta-analyses.

• Randomized trials demonstrate that preoperative radiotherapy followed by surgery is significantly more effective than surgery alone in preventing local recurrence in patients with resectable rectal cancer, and may also improve survival. However, because pathological stage is unknown until surgery is performed, preoperative therapy requires the treatment of most rectal cancer patients and, consequently, exposes many patients who will not benefit to the risk of radiation-induced morbidity and mortality.
• A single trial, using surgery with total mesorectal excision, has shown that preoperative radiotherapy induces a greater than 50% decrease in local recurrence.

• Preoperative radiotherapy (RT) did not significantly increase 30-day postoperative mortality compared with surgery alone (relative risk [RR], 1.33; 95% confidence interval [CI], 0.87 to 2.05; p=0.19). These results showed significant heterogeneity of trial results (X²=23.29; p<0.05). Results were not affected by radiation dose.
• Postoperative morbidity was similar across trials and consisted mainly of delay of perineal wound healing and infection. The pooled results for postoperative morbidity also demonstrated significant heterogeneity (X²=62.74; p<0.001). Results were not different for patients receiving high or low dose radiotherapy or delay to surgery of <7 or >8 days.

• Patients who choose preoperative radiotherapy as a treatment option instead of postoperative combined radiotherapy and chemotherapy need to be made aware that, because pathological stage is unknown until surgery is performed, many patients who will not benefit from treatment will be exposed to the risk of radiation-induced morbidity and mortality.
• Results of trials comparing preoperative radiotherapy to the commonly used postoperative radiotherapy plus chemotherapy are not available for review at this time.
• Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or warranties of any kind whatsoever regarding their content or use or application and disclaims any responsibility for their application or use in any way.

An implementation strategy was not provided.

Living with Illness

Effectiveness

Not applicable: The guideline was not adapted from another source.

2002 Dec (revised 2004 Jan)

Program in Evidence-based Care - State/Local Government Agency [Non-U.S.]

The Practice Guidelines Initiative (PGI) is the main project of the Program in Evidence-based Care (PEBC), a Province of Ontario initiative sponsored by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.

Cancer Care Ontario
Ontario Ministry of Health and Long-Term Care

Provincial Gastrointestinal Cancer Disease Site Group

Not stated

Note: This guideline has been updated. The National Guideline Clearinghouse (NGC) is working to update this summary.

None available

This NGC summary was completed by ECRI on May 14, 2004. The information was verified by the guideline developer on June 2, 2004.